Our goal is to determine whether the relation between free calcium concentration and cardiac myofibrillar activation is varied physiologically and if so, to determine the mechanism of the variation. We call this variation in activation-modulation of calcium control. Three types of potential modulation are studied: 1) Linkage-dependent modulation, 2) Covalent modulation, and 3) Non-covalent modulation. Experiments in which we examine linkage-dependent modulation involve studies aimed at determining whether the number of cross-bridges reactiong with the thin filament alter calcium activation of the myofibrils. Experiments in which we examine covalent modulation involve studies aimed at determining whether isolated and in situ hearts respond to positive and negative inotropic interventions in a way that involves a change in the covalent phosphate content of thin and thick filament regulatory proteins. Experiments in which we examine non-covalent modualtion involve studies of the interaction of ions (H ion, Mg ions, eg.) with the myofibrillar proteins and the effect of this interaction on the calcium control of myofibrillar activation.